Pathophysiology
Adenoma-to-carcinoma sequence: APC loss -> KRAS -> SMAD4/DCC -> TP53 mutations. Alternate pathways: microsatellite instability (MSI-high, Lynch syndrome via MMR gene defects), serrated pathway (BRAF-mutant).
Sources: NCCN Guidelines: Colon Cancer (v3.2025); USPSTF Colorectal Cancer Screening (JAMA 2021;325:1965); ESMO Clinical Practice Guidelines - Metastatic CRC (Ann Oncol 2023;34:10)
Clinical presentation
Right-sided: iron-deficiency anaemia, occult bleeding, fatigue. Left-sided: change in bowel habit, obstruction, haematochezia. Rectal: tenesmus, blood-streaked stool. Weight loss and hepatomegaly suggest metastasis.
Sources: NCCN Guidelines: Colon Cancer (v3.2025); USPSTF Colorectal Cancer Screening (JAMA 2021;325:1965); ESMO Clinical Practice Guidelines - Metastatic CRC (Ann Oncol 2023;34:10)
Screening
Average risk starts at 45 y (USPSTF 2021): colonoscopy every 10 y, or FIT annually, or CT colonography every 5 y, or multi-target stool DNA every 3 y. High risk (family history, IBD, Lynch, FAP) starts earlier and repeats more often.
Sources: NCCN Guidelines: Colon Cancer (v3.2025); USPSTF Colorectal Cancer Screening (JAMA 2021;325:1965); ESMO Clinical Practice Guidelines - Metastatic CRC (Ann Oncol 2023;34:10)
Diagnosis and staging
Colonoscopy with biopsy is diagnostic; complete tattooing localises lesions. Staging: CT chest/abdomen/pelvis, CEA baseline. Rectal cancer requires pelvic MRI and endorectal ultrasound. Test tumour for MMR/MSI and RAS/BRAF status.
Sources: NCCN Guidelines: Colon Cancer (v3.2025); USPSTF Colorectal Cancer Screening (JAMA 2021;325:1965); ESMO Clinical Practice Guidelines - Metastatic CRC (Ann Oncol 2023;34:10)
Management
Stage I-III colon: resection with adequate lymphadenectomy; adjuvant FOLFOX for stage III. Rectal: neoadjuvant chemoradiotherapy (or total neoadjuvant therapy) then surgery. Metastatic: chemotherapy (FOLFOX/FOLFIRI) plus targeted agents (anti-EGFR if RAS/BRAF wild-type left-sided; anti-VEGF; immunotherapy for MSI-high).
Sources: NCCN Guidelines: Colon Cancer (v3.2025); USPSTF Colorectal Cancer Screening (JAMA 2021;325:1965); ESMO Clinical Practice Guidelines - Metastatic CRC (Ann Oncol 2023;34:10)
